BACKGROUND: Radiation therapy is an important component in the treatment of medulloblastoma; however, in many patients, it is associated with risk of late adverse events. Proton radiation therapy has potential to reduce the risk of adverse events compared with conventional radiation, but it is associated with a higher treatment cost. The objective of the current study was to assess the cost-effectiveness of proton therapy compared with conventional radiation therapy in the treatment of childhood medulloblastoma. METHODS: The consequences of radiation therapy were evaluated using a Markov simulation model. Children age 5 years with medulloblastoma were followed. The patients were at risk of several types of adverse events, including hearing loss, intelligence quotient (IQ) loss, hypothyroidism, growth hormone deficiency (GHD), osteoporosis, cardiac disease, and secondary malignancies. The patients also were at risk of death and were divided into risk groups for normal death, death due to tumor recurrence, treatment-related cardiac death, treatment-related subsequent tumor death, or treatment-related other death. A review of the literature was conducted to estimate the parameters in the model. RESULTS: The base-case results showed that proton therapy was associated with 23,600 in cost savings and 0.68 additional quality-adjusted life-years per patient. The analyses showed that reductions in IQ loss and GHD contributed to the greatest part of the cost savings and were the most important parameters for cost-effectiveness. CONCLUSIONS: The results of the current study indicated that proton radiation therapy can be cost-effective and cost-saving compared with conventional radiation therapy in the treatment of children with medulloblastoma if the appropriate patients are selected for the therapy. However, there have been few long-term follow-up studies, and more much information on the long-term consequences of radiation therapy is needed.